Cephalosporin derivatives

ABSTRACT

A cephalosporin derivative having the formula: ##STR1## wherein R 1  is a substituted amino group, X is an alkylene group, R 2  is an aryl or heterocyclic group which may be substituted and R 3  is a hydrogen atom, a negative charge or a residue of an ester which can form a pharmaceutically acceptable ester hydrolyzable in a living body; or a pharmaceutically acceptable salt thereof.

This is a continuation of application Ser. No. 161,100, filed on Feb.26, 1988, now U.S. Pat. No. 4,918,070.

The present invention relates to novel cephalosporin derivatives whichare useful in the pharmaceutical fields, a process for their preparationand antibacterial agents.

The cephalosporin antibacterial agents have been widely used for thetreatment of diseases caused by pathogenic bacteria in human andanimals. For example, they are particularly useful for the treatment ofinfectious diseases caused by bacteria having resistance againstPenicillin type antibacterial agents and for the treatment of infectiousdiseases of patients sensitive to Penicillin. Further, the cephalosporinantibacterial agents have low toxicity against animal cells, and thusthey are superior also in the safety. Under the circumstances, manyattempts have been made to provide cephalosporin antibacterial agentshaving stronger antibacterial activities and excellent safety.

Among such attempts, cephalosporin derivatives wherein the substituentat the 3-position of the cephalosporin nucleus is directly replaced byan oxygen atom are known and disclosed in Japanese Unexamined PatentPublications No. 55687/1974, No. 108287/1975, No. 56489/1976, No.63191/1976, No. 103493/1978, No. 76089/1984, No. 40292/1986, No.130293/1986 and No. 19594/1987. However, most of the compounds disclosedin these publications are used merely as intermediates, or the compoundssimply have a lower alkoxy group such as a methoxy group as thesubstituent at the 3-position of the cephalosporin nucleus. Thus, thecephalosporin derivatives having at the 3-position of the cephalosporinnucleus an alkoxy group substituted by an aryl or heterocyclic groupwhich may be substituted, have not been disclosed.

It is an object of the present invention to provide novel cephalosporinderivatives having not only excellent antibacterial activities but alsoexcellent properties in the safety.

The present inventors have conducted an extensive research for novelcephalosporin derivatives having excellent antibacterial activities, andhave found that a series of cephalosporin derivatives having at the3-position of the cephalosporin nucleus an alkoxy group substituted byan aryl or heterocyclic group which may be substituted, show excellentantibacterial activities. The present invention has been accomplishedbased on the discovery.

The present invention provides a compound having the formula: ##STR2##wherein R¹ is a substituted amino group, X is an alkylene group, R² isan aryl or heterocyclic group which may be substituted and R³ is ahydrogen atom, a negative charge or a residue of an ester which can forma pharmaceutically acceptable ester hydrolyzable in a living body; or apharmaceutically acceptable salt thereof.

Further, the present invention provides a process for preparing thecompound of the formula I, or a pharmaceutically acceptable saltsthereof, which comprises reacting a compound having the formula:##STR3## wherein R^(1') represents R¹ as defined above or R¹ with itsfunctional group protected, R^(3') is a hydrogen atom, acarboxyl-protecting group or a residue of an ester which can form apharmaceutically acceptable ester hydrolyzable in a living body, or asalt thereof, with a compound having the formula:

    HO--X--R.sup.2'                                            (III)

wherein X is an alkylene group and R^(2') is an aryl or heterocyclicgroup which may be substituted, to form a compound having the formula:##STR4## wherein R^(1'), R^(2'), R^(3') and X are as defined above, andoptionally conducting one or more of the following steps:

(i) when R^(2') is a heterocyclic group, a step of introducing asubstituent which may be protected to the heterocyclic group

(ii) a step of removing any protecting group

(iii) a step of converting the compound in the free form to a saltthereof, and

(iv) a step of forming a pharmaceutically acceptable ester hydrolyzablein a living body.

The present invention also provides an antibacterial agent comprising anantibacterially effective amount of the compound of the formula I or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The definition of various terms referred to in this specification andsome specific examples falling within such terms will be given.

The substituted amino group, means an amino group substituted by an acylgroup, which is usually used as a substituent in cephalosporin andpenicillin compounds. The acyl group includes an aliphatic acyl group,an acyl group having an aromatic ring (hereinafter referred to as anaromatic acyl group) and an acyl group having a heterocyclic ring(hereinafter referred to as a heterocyclic acyl group).

The aliphatic acyl group may be a lower or higher alkanoyl group havingfrom 1 to 20 carbon atoms such as a formyl group, an acetyl group, asuccinyl group, a hexanoyl group, a heptanoyl group or a stearoyl group,a lower alkoxycarbonyl group having from 2 to 8 carbon atoms such as amethoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonylgroup, a tert-pentyloxycarbonyl group or a heptyloxycarbonyl group, alower alkanesulfonyl group having from 1 to 4 carbon atoms such as amethanesulfonyl group, an ethanesulfonyl group or a propanesulfonylgroup, a lower alkenylthioalkanoyl group having from 4 to 8 carbon atomssuch as a vinylthioacetyl group, an allylthioacetyl group, anallylthiopropionyl group or a butenylthioacetyl group, a loweralkylthioalkanoyl group having from 3 to 8 carbon atoms such as amethylthioacetyl group, an ethylthioacetyl group or amethylthiopropionyl group, or an unsaturated cycloalkenylalkanoyl grouphaving from 8 to 10 carbon atoms such as a cyclohexenylacetyl group orcyclohexadienylacetyl group.

The aromatic acyl group may be an aroyl group having from 7 to 12 carbonatoms such as a benzoyl group, a toluoyl group or a naphthoyl group, anarylalkanoyl group having from 8 to 10 carbon atoms such as aphenylacetyl group or a phenylpropionyl group, an aryloxycarbonyl grouphaving from 7 to 12 carbon atoms such as a phenoxycarbonyl group or anaphthyloxycarbonyl group, an arylalkoxycarbonyl group having from 8 to10 carbon atoms such as a benzyloxycarbonyl group or aphenethyloxycarbonyl group, or an aryloxyalkanoyl group having from 8 to10 carbon atoms such as a phenoxyacetyl group or a phenoxypropionylgroup.

The heterocyclic acyl group may be a heterocyclic carbonyl group such asa thenoyl group, a furoyl group or a nicotinoyl group, a heterocyclicalkanoyl group such as a thienylacetyl group, a thiazolylacetyl group, athiadiazolylacetyl group, a dithiinylacetyl group, a pyridylacetylgroup, a pyrimidinylacetyl group, a triazolylacetyl group, a tetrazolylacetyl group, a furylacetyl group, an oxazolylacetyl group or athiadiazolylpropionyl group, or a heterocyclic oxy or thioalkanoyl groupsuch as a pyridyloxyacetyl group, a pyridylthioacetyl group or apyridyloxypropionyl group.

The above-mentioned acyl group may have one or more substituents whichmay be the same or different. As the substituent, a halogen atom, analkyl group which may be substituted, a hydroxyl group, a methoxy group,an ethoxy group, a fluoromethoxy group, a trifluoromethoxy group, adifluoromethoxy group, a formyloxy group, an acetoxy group, afluoroacetoxy group, a carbamoyl group, an N-methylcarbamoyl group, anN,N-dimethylcarbamoyl group, a carbamoyloxy group, anN,N-dimethylcarbamoyloxy group, an N-methylcarbamoyloxy group, an aminogroup, an acetamide group, a formamide group, a fluoroacetamide group, acarboxyl group, a sulfo group, a sulfamoyl group, a cyano group,a═N--OR¹³ group wherein R¹³ is a hydrogen atom or a lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, aryl, aralkyl or heterocyclic groupwhich may be substituted, or a ##STR5## group wherein each of R¹⁴ andR¹⁵ the same or different is a hydrogen atom, a halogen atom or a loweralkyl, aryl or aralkyl group which may be substituted.

The halogen atom includes a fluorine atom, a chlorine atom, a bromineatom and an iodine atom.

The lower alkyl group which may be substituted, may be an alkyl grouphaving from 1 to 6 carbon atoms such as a methyl group, an ethyl group,a propyl group, an isopropyl group, a butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group,a hexyl group or an isohexyl group, which may be substituted by one ormore substituents such as a halogen atom, a hydroxyl group, a methoxygroup, an ethoxy group, a propoxy group, a fluoromethoxy group, adifluoromethoxy group, a trifluoromethoxy group, a formyloxy group, anacetoxy group, a fluoroacetoxy group, an N-methylcarbamoyl group, acarbamoyl group, an N-methylcarbamoyloxy group, an N,N-dimethylcarbamoylgroup, an N,N-dimethylcarbamoyloxy group, an amino group, a methylaminogroup, a dimethylamino group, a formamido group, an acetamido group, afluoroacetamido group, a carboxyl group, a methoxycarbonyl group, anethoxycarbonyl group, a sulfo group, a sulfamoyl group, a cyano group, aformyl group, an acetyl group, a fluoroacetyl group, a diethylaminogroup, an ethylamino group, a methylthio group, an ethylthio group, apropylthio group, a fluoromethylthio group, a 2-fluoroethylthio group, a1-fluoroethylthio group, a tetrazolyl group, a 1-methyltetrazolyl group,a thiazolyl group, a 2-aminothiazolyl group, a5-amino-1,2,4-thiadiazolyl group, a 1,2,4-thiadiazolyl group, a1,2,3,-thiadiazolyl group, an imidazolyl group, a thienyl group, afuranyl group, a 2-aminoxazolyl group, an isothiazolyl group, anisoxazolyl group, a quinolyl group, an isoquinolyl group, a pyridylgroup, a 3,4-dihydroxy-6-pyridyl group, a piperazinyl group, a piperidylgroup, a pyrrolidinyl group, a pyrrolyl group, a morpholinyl group, abenzothiazolyl group or a benzimidazolyl group.

The cycloalkyl group which may be substituted, may be a cycloalkyl grouphaving from 3 to 6 carbon atoms such as a cyclopropyl group, acyclobutyl group, a cyclopentyl group or a cyclohexyl group, which maybe substituted by one or more substituents such as a carbamoyl group, acarboxyl group, an amino group, a methylamino group, a dimethylaminogroup, a sulfo group, a hydroxyl group or a cyano group.

The alkenyl group which may be substituted, may be an alkenyl grouphaving from 2 to 6 carbon atoms such as a vinyl group, an allyl group, a1-propenyl group, a 2-propenyl group, an isopropenyl group, a 1-butenylgroup, a 2-butenyl group, a 1-pentenyl group or a 1-hexenyl group, whichmay be substituted by one or more substituents such as a halogen atom, acarboxyl group, an amino group, a sulfo group, a hydroxyl group, acarbamoyl group or a cyano group.

The alkynyl group which may be substituted, may be an alkynyl grouphaving from 2 to 6 carbon atoms such as an ethynyl group, a 1-propynylgroup, a propargyl group, a 1-butynyl group, a 1-pentynyl group or a1-hexynyl group which may be substituted by one or more substituentssuch as a halogen atom, a hydroxyl group, an amino group, a carboxylgroup, a carbamoyl group, a sulfo group or a cyano group.

The aryl group which may be substituted, may be an aryl group havingfrom 6 to 10 carbon atoms such as a phenyl or naphthyl group, which maybe substituted by one or more substituents such as a halogen atom, amethyl group, a hydroxymethyl group, a fluoromethyl group, atrifluoromethyl group, an ethyl group, a bromomethyl group, adifluoromethyl group, a hydroxyl group, an aminomethyl group, acarboxymethyl group, a carbamoylmethyl group, a sulfomethyl group, anN-methylaminomethyl group, a methoxy group, an ethoxy group, a propoxygroup, a fluoromethoxy group, an amino group, a methylamino group, adimethylamino group, an ethylamino group, a propylamino group, aformamido group, an acetamido group, a propionylamino group, a formyloxygroup, an acetoxy group, a propionyloxy group, a carboxyl group, acarbamoyl group, an N-methylcarbamoyl group, an N,N-dimethylcarbamoylgroup, a methoxycarbamoyl group, an ethoxycarbamoyl group, a sulfamoylgroup, a sulfo group, a cyano group or a nitro group.

The heterocyclic group which may be substituted, may be a monocyclic ordicyclic heterocyclic group containing from 1 to 4 hetero atoms selectedfrom the group consisting of a nitrogen atom, a sulfur atom and anoxygen atom, such as a 1,2,3-thiadiazolyl group, a 1,3,4-thiadiazolylgroup, a 1,2,4-thiadiazolyl group, a 1,2,3-triazolyl group, a1,3,4-triazolyl group, a tetrazolyl group, a thiazolyl group, anisothiazolyl group, an oxazolyl group, an isoxazolyl group, animidazolyl group, a pyridyl group, a pyrimidinyl group, a thienyl group,a furanyl group, a piperazinyl group, a piperidyl group, a morpholinylgroup, a pyrrolidinyl group, a quinolyl group, an isoquinolyl group, abenzothiazolyl group or a benzimidazolyl group, which may be substitutedby one or more substituents such as a halogen atom, a methyl group, anethyl group, a propyl group, a hydroxymethyl group, an aminomethylgroup, a sulfomethyl group, a carboxymethyl group, a cyanomethyl group,a fluoromethyl group, a chloromethyl group, a difluoromethyl group, atrifluoromethyl group, a carbamoylmethyl group, anN-methylcarbamoylmethyl group, a sulfamoylmethyl group, an oxo group, anN-methylaminomethyl group, an amino group, a methylamino group, adimethylamino group, an ethylamino group, a methoxy group, an ethoxygroup, a fluoromethoxy group, a difluoroethoxy group, a trifluoroethoxygroup, a sulfamoyl group, a carboxyl group, a methoxycarbonyl group, acyano group, a nitro group, a vinyl group, an allyl group, a propargylgroup, an ethynyl group, an acetoxy group, a formyloxy group, acarbamoyloxy group, an N-methylcarbamoyloxy group, an acetamide group, aformamide group, an acetyl group, a fluoroacetyl group, a difluoroacetylgroup, a trifluoroacetyl group, a hydroxyl group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group or a cyclohexyl group. When apositive charge arises due to the existence of a substituent in anitrogen atom of the heterocyclic ring, an intramolecular salt or anintermolecular salt is formed.

The aralkyl group which may be substituted includes an aralkyl grouphaving from 7 to 12 carbon atoms such as a benzyl phenethyl group or anaphthylmethyl group, which may be substituted by one or moresubstituents such as a methyl group, an ethyl group, a propyl group, ahalogen atom, a fluoromethyl group, a difluoromethyl group, atrifluoromethyl group, a carboxymethyl group, an aminomethyl group, asulfomethyl group, a carbamoylmethyl group, an N-methylaminomethylgroup, a methoxy group, an ethoxy group, a fluoroethoxy group, adifluoroethoxy group, a trifluoroethoxy group, a hydroxyl group, aformyloxy group, an acetoxy group, a trifluoroacetoxy group, an aminogroup, a methylamino group, an ethylamino group, a dimethylamino group,a diethylamino group, a formamido group, an acetamido group, a carboxylgroup, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoylgroup, an N-methylcarbamoyl group, an N,N-dimethylcarbamoyl group, asulfo group, a cyano group or a nitro group.

The alkylene group may be a straight chain, branched chain or cyclicalkylene group having from 1 to 6 carbon atoms such as a methylenegroup, an ethylene group, an ethylidene group, an isopropylidene group,a propylene group, a trimethylene group, a tetramethylene group, a1,2-cyclopentylene group, a 1,3-cyclopentylene group, a1,2-cyclohexylene group, a 1,3-cyclohexylene group or a1,4-cyclohexylene group.

The carboxyl-protecting group may be a carboxyl-protecting group whichcan be easily removed by an acid hydrolysis, catalytic reduction etc.such as a tert-butyl group, a phenyl group, a methoxymethyl group, anethoxymethyl group, a benzyl group, a p-methoxybenzyl group, ap-nitrobenzyl group or a benzhydryl group.

The amino-protecting group may be an amino-protecting group which can beeasily removed by an acid hydrolysis, a catalytic reduction, etc., suchas a trityl group, a formyl group, a chloroacetyl group, atrifluoroacetyl group, a tert-butoxycarbonyl group, a trimethylsilylgroup or a tert-butyldimethylsilyl group.

The residue of an ester which can form a pharmaceutically acceptableester hydrolyzable in a living body, may be a lower alkanoyloxymethylgroup such as an acetoxymethyl group, a propionyloxymethyl group or apivaloyloxymethyl group; a 1-(lower alkoxycarbonyloxy)ethyl group suchas a 1-(methoxycarbonyloxy)ethyl group, a 1-(ethoxycarbonyloxy)ethylgroup or a 1-(tert-butoxycarbonyloxy)ethyl group; a5-substituted-2-oxo-1,3-dioxol-4-ylmethyl group such as5-methyl-2-oxo-1,3-dioxol-4-ylmethyl group or a5-phenyl-2-oxo-1,3-dioxol-4-ylmethyl group; a 1-phthalidyl group or a5-cyano-1-phthalidyl group.

In the compound of the formula I of the present invention, R¹ ispreferably an amino group which is substituted by an acyl group, such asa (2-fluoro-2-carbamoylvinylthio)acetyl group, a2-difluoromethylthioacetyl group, a 2-phenylacetyl group, a2-amino-2-phenylacetyl group, a 2-amino-2-(4-hydroxyphenyl)acetyl group,a 2-carboxy-2-phenylacetyl group, a 2-carboxy-2-(4-hydroxyphenyl)acetylgroup, a2-(4-hydroxyphenyl)-2-[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonylamino]acetylgroup, a 2-phenyl-2-[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonylamino]acetyl group, a2-sulfo-2-phenylacetyl group, a 2-hydroxy-2-phenylacetyl group, a2-(1,4-cyclohexadienyl)acetyl group, a2-amino-2-(1,4-cyclohexadienyl)acetyl group, a 2-(2-thienyl)acetylgroup, a 2-(2-furanyl)acetyl group, a 2(2-aminomethylphenyl)acetylgroup, a 2-carboxy-2-(3-thienyl)acetyl group, a 2-tetrazolylacetylgroup, a 2-methoxyimino-2-(2-thienyl)acetyl group, a2-methoxyimino-2-(2-furanyl)acetyl group, a 2-(4-pyridylthio)acetylgroup, a 2-(4-pyridyloxy)acetyl group, a 2-hydroxyimino-2-phenylacetylgroup, a 2-cyanomethylthioacetyl group, a 2-(2-fluorovinylthio)acetylgroup, a 2-trifluoromethylthioacetyl group, a2-(2-aminothiazol-4-yl)acetyl group, a 2-methoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-ethoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-propoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-butoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-sec-butoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-tert-butoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-pentyloxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-hydroxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-cyclopropoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-cyclobutoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-cyclohexyloxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-(1-carboxy-1-cyclopropoxyimino)- 2-(2-aminothiazol-4-yl)acetyl group,a 2 (1-carboxy-1-cylcobutoxyimino)-2-(2-aminothiazol-4-yl)acetyl group,a 2-(1-carboxy-1-cyclopentyloxyimino) -2-(2-aminothiazol-4-yl) acetylgroup, a 2-(1-carboxy-1-cyclohexyloxyimino)-2-(2-aminothiazol-4-yl)acetyl group, a 2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetylgroup, a 2-(2-carboxyethoxyimino)-2-(2-aminothiazol-4-yl) acetyl group,a 2-(1-carboxyethoxyimino)-2-(2-aminothiazol- 4-yl)acetyl group, a2-(1-carboxy-1-methylethoxyimino)-2-(2-aminothiazol-4-yl) acetyl group,a 2-(1-carboxy-1-ethenyloxyimino)-2-(2-aminothiazol-4-yl) acetyl group,a 2-(2-carboxymethyl-1-ethenyloxyimino)-2-(2-aminothiazol-4-yl) acetylgroup, a 2-fluoromethoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-bromomethoxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-(2-fluoroethoxyimino)-2-(2-aminothiazol-4-yl) acetyl group, a2-(2-chloroethoxyimino)-2-(2-aminothiazol-4-yl) acetyl group, a2-(1-fluoro-1-methylethoxyimino)-2-(2-aminothiazol-4-yl) acetyl group, a2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetyl group, a2-(3,4-dihydroxybenzyloxyimino)-2-(2-aminothiazol-4-yl) acetyl group, a2-(α-carboxy-3,4-dihydroxybenzyloxyimino) -2-(2-aminothiazol-4-yl)acetylgroup, a 2-(α-carboxybenzyloxyimino)-2-(2-aminothiazol-4-yl) acetylgroup, a 2-(2-carboxymethylbenzyloxyimino)-2-(2-aminothiazol-4-yl)acetyl group, a 2-(2-carboxybenzyloxyimino)-2-(2-aminothiazol-4-yl)acetyl group, a 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetylgroup, a 2-(2-fluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl group, a2-(1-carboxy-1-ethenyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl) acetylgroup, a2-(1-carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl group, a2-(α-carboxy-3,4-dihydroxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetylgroup, a 1-(2-aminothiazol-4-yl)-1-propenylcarbonyl group, a2-benzylidene-2-(2 -aminothiazol-4-yl) acetyl group, a2-chloromethylene-2-(2-aminothiazol-4-yl) acetyl or a2-fluoromethylene-2-(2-aminothiazol-4-yl)acetyl group.

The --O--X--R² group of the present invention is preferably a benzyloxygroup, a 4-cyanobenzyloxy group, a 4-nitrobenzyloxy group, a4-carboxybenzyloxy group, a 4-carbamoylbenzyloxy group, a3,4-dihydroxybenzyloxy group, a thiazol-4-ylmethoxy group, athiazol-2-ylmethoxy group, a thiazol-5-ylmethoxy group, a4-methylthiazol-2-ylmethoxy group, a 2-methylthiazol-5-ylmethoxy group,a 1,2,3-thiadiazol-4-ylmethoxy group, a 1,2,4-thiadiazol-3-ylmethoxygroup, a 1,3,4-thiadiazol-2-ylmethoxy group, a1-methylimidazol-2-ylmethoxy group, a 2-pyrrolidon-5-ylmethoxy group, a1-methyl-2-pyrrolidon-5-ylmethoxy group, a tetrazol-5-ylmethoxy group, a1,3,4-triazol-2-ylmethoxy group, a 2-pyridylmethoxy group, a3-pyridylmethoxy group, a 4-pyridylmethoxy group, a1-methyl-2-pyridiniomethoxy group, a 1-methyl-3-pyridiniomethoxy group,a 1-methyl-4-pyridiniomethoxy group, a 1-ethyl-2-pyridiniomethoxy group,a 1-ethyl-4-pyridiniomethoxy group, a 1-propyl-4-pyridiniomethoxy group,a 1-allyl-2-pyridiniomethoxy group, a 1-allyl-4-pyridiniomethoxy group,a 1-carboxymethyl-3-pyridiniomethoxy group, a1-carboxymethyl-4-pyridiniomethoxy group, a1-carbamoylmethyl-2-pyridiniomethoxy group, a1-carbamoylmethyl-4-pyridiniomethoxy group, a 1-(2-pyridyl)ethoxy group,a 1-(3-pyridyl)ethoxy group, a 1-(4 -pyridyl)ethoxy group, a1-(1-methyl-4-pyridinio)ethoxy group, a 1-(1-methyl-3-pyridinio)ethoxygroup, a 1-(1-methyl-2-pyridinio)ethoxy group, a 2-(2-pyridyl)ethoxygroup, a 2-(3-pyridyl)ethoxy group, a 2-(4-pyridyl)ethoxy group, a2-(1-methyl-2-pyridinio)ethoxy group, a 2-(1-methyl-3-pyridinio)ethoxygroup, a 2-(1-methyl-4-pyridinio)ethoxy group, a3,4-dihydroxy-1-methyl-6-pyridiniomethoxy group, a3,4-dihydroxy-1-(2-fluoroethyl)-6-pyridiniomethoxy group, a2-chloro-1-methyl-4-pyridiniomethoxy group, a1,2-dimethyl-4-pyridiniomethoxy group, a2-carbamoyl-1-methyl-4-pyridiniomethoxy group, a3-carboxy-1-methyl-5-pyridiniomethoxy group, a4-hydroxy-1-methyl-2-pyridiniomethoxy group, or a1-(2-methoxy-4-pyridyl)ethoxy group.

The pharmaceutically acceptable salt of the compound of the formula Imay be a salt with an alkali metal such as sodium, potassium or lithium,a salt with an alkaline earth metal such as calcium or magnesium, a saltwith an organic amine such as N,N-dibenzylethylenediamine, ethanolamineor triethylamine, a salt with an inorganic acid such as hydrochloricacid, nitric acid sulfuric acid or phosphoric acid, a salt with anorganic acid such as acetic acid, citric acid or tartaric acid, a saltwith an organic sulfonic acid such as methanesulfonic acid orp-toluenesulfonic acid or a salt with an amino acid such as asparticacid, glutamic acid or lysine.

Now, the process for the preparation of the compounds of the presentinvention will be described. The compound of the formula I of thepresent invention can be prepared by reacting a compound having theformula: ##STR6## wherein R^(1') represents R¹ as defined above or R¹with its functional group protected, R^(3') is a hydrogen atom, acarboxyl-protecting group or a residue of an ester which can form apharmaceutically acceptable ester hydrolyzable in a living body, or asalt thereof, with a compound having the formula:

    HO--X--R.sup.2'                                            (III)

wherein X is an alkylene group and R^(2') is an aryl or heterocyclicgroup which may be substituted, to form a compound having the formula:##STR7## wherein R^(1'), R^(2'), R^(3') and X are as defined above, andoptionally conducting one or more of the following steps:

(i) when R^(2') is a heterocyclic group, a step of introducing asubstituent which may be protected to the heterocyclic group

(ii) a step of removing any protecting group

(iii) a step of converting the compound in the free form to a saltthereof, and

(iv) a step of forming a pharmaceutically acceptable ester hydrolyzablein a living body.

The reaction of the compound of the formula II with the compound of theformula III to produce the compound of the formula IV, may be conductedin an organic solvent which does not adversely affect the reaction, forexample, in an aromatic hydrocarbon such as benzene or toluene, in anether such as diethyl ether, tetrahydrofuran or dioxane, in achlorinated hydrocarbon such as methylene chloride or chloroform, or anacid amide such as N,N-dimethylformamide or N,N-dimethylacetamide, inthe presence of an azodicarboxylate reagent, and a trialkylphosphine ora triarylphosphine.

The azodicarboxylate reagent used in this reaction may bedimethylazodicarboxylate, diethylazodicarboxylate ordiisopropylazodicarboxylate, and is preferably diethylazodicarboxylate.The trialkylphosphine or the triarylphosphine may be triethylphosphine,tributylphosphine or triphenylphosphine, and is preferablytriphenylphosphine.

As the reaction conditions of this step, an amount of each startingmaterials and reagents may suitably be selected. Preferably, the molarratio of the compound of the formula II, the compound of the formulaIII, the azodicarboxylate reagent and the phosphene is about 1:1:1. Thereaction temperature may suitably be selected from the range of from-50° C. to the reflux temperature. The reaction temperature ispreferably from -30° C. to room temperature, and the reaction time maybe from 5 minutes to 24 hours.

When R^(2') of the compound of the formula IV thus obtained is aheterocyclic group, the step of introducing a substituent to theheterocyclic group, may be conducted by reacting the compound of theformula IV with an alkylating agent in a non-aqueous solvent such asmethylene chloride, chloroform, tetrahydrofuran, acetone, acetonitrile,N,N-dimethylformamide or N,N-dimethylacetamide, or in a mixture of suchsolvents.

The alkylating agent used in this step, may be a lower alkyl iodide suchas methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide or butyliodide, an alkenyl iodide such as an allyl iodide 1-butenyl iodide,dimethyl sulfate, an alkyl sulfonate which may be substituted by ahalogen atom such as methylfluoro sulfonate, methyltrifluoromethanesulfonate or ethyltrifluoromethane sulfonate, a benzhydryl iodoacetateor iodoacetamide.

The reaction of this step usually conducted at a temperature from -10°to 50° C., preferably at room temperature, for 1 to 48 hours, preferablyfor 24 hours.

If the products prepared by the above-mentioned steps have a protectinggroup, the protecting group is removed by a method suitably selected,depending upon the type of the protecting group, from conventionalmethod disclosed in, for example, Protective Groups in Organic Synthesispublished in 1981. For instance, the amino-protecting group is removedas follows: a tert-butoxycarbonyl group or a trityl group is removed byan acid, a 2,2,2-trichloroethoxycarbonyl group is removed by zinc and anacid, and a p-nitrobenzyloxycarbonyl group is removed by a catalyticreduction. For instance, the hydroxyl-protecting group is removed asfollows: a formyl group or a trifluoroacetyl group is removed bypotassium hydrogen carbonate in hydrous methanol, a tetrahydropyranylgroup is removed by dilute hydrochloric acid, and a2,2,2-trichloroethoxycarbonyl group is removed by zinc and an acid. Forinstance, the carboxyl-protecting group is removed as follows: abenzhydryl group or a p-methoxybenzyl group is removed by an acid suchas trifluoroacetic acid in the presence of anisole, a 2-methylsulfonylgroup is removed by an alkali, a trimethylsilyl group or atert-butyldimethylsily group is removed by water or a hydrous alcohol, a2,2,2-trichloroethyl group is removed by zinc and an acid, and ap-nitrobenzyl group is removed by reduction.

The product obtained from each step can be purified by columnchromatography, extraction with a solvent, precipitation,recrystallization, etc. Further, the product can be converted to adesired salt or ester by a conventional method, if necessary.

The starting material of the formula II of the present invention can beprepared by reacting 7-amino-3-hydroxy-3-cephem-4-carboxylic acidprepared by a method described in Helvetica Chimica Acta, vol. 57, page1919 (1974) with a desired active derivative such as a mixed acidanhydride, an acid halide, an azide or an active ester. As the compoundof the formula III, a compound commercially available or a compoundreadily prepared by a conventional method can be used.

The compound of the present invention shows excellent antibacterialactivities, and is useful for a medicine. It can be used for thetreatment or prevention of infectious diseases caused by bacteria, suchas respiratory infectiousness, infectiousness of the genito-urinarytract, suppurative diseases and surgical infectiousness.

As the administration method, non-oral administration such as injectioninto veins, injection into muscles or suppositories, or oraladministration such as tablets, powders, capsules, or syrups may bementioned. Such formulations are prepared by a usual method in thisfield, and may contain additives which are commonly used, such asassisting agents, stabilizers, wetting agents and emulsifying agents.The dose may vary depending upon the age, sex, weight, sensitivity,administration method, administration period or interval, condition ofthe patient, properties, method or type of formulations and type of theactive ingredient, and should be determined by a doctor. The daily doseis usually within a range of from 1 to 100 mg/kg, which is preferablyadministered in 2 to 4 times per day, each time with a dose of from 5 to30 mg/kg.

To demonstrate the usefulness of the compounds of the present invention,the in vitro antibacterial activities of the compounds of the presentinvention against various microorganisms were measured by the followingagar plate dilution method. One platinum loopfull of each testmicroorganism incubated overnight in Mueller Hinton broth, wasinoculated to Mueller Hinton agar (inoculum size: 10⁶ CFU/ml). Suchculture media containing various antibiotics in various concentrationswere prepared. After incubation at 37° C. for 16 hours, the minimuminhibitory concentrations (MIC: μg/ml) were measured. The results areshown in the following Table 1.

                                      TABLE 1                                     __________________________________________________________________________            1                                                                                 Minimum Inhibitory Concentration (μg/ml, 10.sup.6 CFU/ml,                  MH agar)                                                                      Compound                                                                            Compound                                                                            Compound                                                                            Compound                                                                            Compound                                                                            Compound                                                                            Compound                      Test microorganism                                                                        of Ex. 1                                                                            of Ex. 4                                                                            of Ex. 12                                                                           of Ex. 14                                                                           of Ex. 16                                                                           of Ex. 18                                                                           of Ex. 22                     __________________________________________________________________________    S. aureus 209P NIHJ-JCl                                                                   0.780 12.5  0.780 3.12  3.12  3.12  50.0                          E. coli NIHJ JC2                                                                          0.200 0.390 0.780 0.390 0.200 0.390 0.050                         K. pneumoniae PCI-602                                                                     <0.006                                                                              0.050 0.0125                                                                              <0.006                                                                              <0.006                                                                              0.0125                                                                              0.025                         P. vulgaris HX-19                                                                         0.050 0.0125                                                                              0.025 0.050 <0.006                                                                              0.100 0.025                         S. marcescens IAM 1184                                                                    0.100 0.025 0.390 0.100 0.200 0.390 0.0125                        E. cloacae 963                                                                            0.200 0.039 0.780 0.200 0.200 0.390 0.100                         __________________________________________________________________________                Minimum Inhibitory Concentration (μg/ml, 10.sup.6 CFU/ml,                  MH agar)                                                                      Compound                                                                            Compound                                                                            Compound                                                                            Compound                                                                            Compound                                                                            Compound                                                                            Compound                      Test microorganism                                                                        of Ex. 32                                                                           of Ex. 36                                                                           of Ex. 37                                                                           of Ex. 38                                                                           of Ex. 40                                                                           of Ex. 44                                                                           of Ex. 51                     __________________________________________________________________________    S. aureus 209P NIHJ-JCl                                                                   0.039 6.25  1.56  0.039 1.56  0.200 3.12                          E. coli NIHJ JC2                                                                          0.100 0.050 0.025 0.039 0.390 0.390 0.200                         K. Pneumoniae PCI-602                                                                     0.025 0.0125                                                                              <0.006                                                                              0.025 0.050 0.050 0.025                         P. vulgaris HX-19                                                                         0.200 0.050 0.025 0.390 0.0125                                                                              0.200 0.050                         S. marcescens IAM 1184                                                                    0.050 0.025 <0.006                                                                              0.100 0.100 0.200 0.100                         E. cloacae 963                                                                            0.100 0.050 0.025 0.039 0.390 0.200 0.100                         __________________________________________________________________________

Now, the present invention will be described with reference to Examples.However, it should be understood that the present invention is by nomeans restricted by these specific Examples.

EXAMPLE 1 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate

2.29 g (3.01 mmol) of p-methoxybenzyl7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylateand 982 mg (3.75 mmol) of triphenylphosphine were dissolved in 48 ml oftetrahydrofuran, and a solution of 408 mg (3.74 mmol) of4-pyridinemethanol in 24 ml of tetrahydrofuran was added thereto at roomtemperature under nitrogen atmosphere. Then, a solution of 0.58 ml (3.67mmol) of diethylazodicarboxylate in 24 ml of tetrahydrofuran wasdropwise added thereto at room temperature, and the mixture was stirredfor 2 hours at the same temperature. The solvent was distilled off. Theresidue was dissolved in ethyl acetate, washed sequentially with water,a saturated sodium hydrogencarbonate aqueous solution and a saturatedsodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent was distilled off and the residue was purified by silica gelcolumn chromatography (Wakogel C-300, elution with 1%methanol-chloroform) to obtain 1.46 g (yield: 56.9%) of p-methoxybenzyl7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylateas a light yellow powder. 660 mg (0.774 mmol) of this powder wasdissolved in 4.1 ml of dichloromethane and 0.9 ml of anisole, and 6.6 mlof trifluoroacetic acid was dropwise added thereto under cooling withice. The mixture was stirred for 1 hour at the same temperature. Thesolvent was distilled off, and isopropyl ether was added to the residueto obtain the trifluoroacetate of the above-identified compound as apowder. This trifluoroacetate was dissolved in water and adjusted topH6.5 with a sodium hydrogencarbonate aqueous solution. The solution waspurified by reversed phase column chromatography (Chemco LC-SORB,SP-B-ODS, elution with 20% methanol aqueous solution) and freeze-driedto obtain 221 mg (yield: 55.7%) of the above-identified compound.

MP: 175° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1670, 1620, 1540

NMR(DMSO-d₆) δ: 3.45(2H, br), 3.86(3H, s), 5.02(1H, d, J=4.5Hz),5.03(2H, s), 5.5(1H, dd, J=4.5Hz & 8Hz), 6.75(1H, s), 7.22(2H, br),7.41(2H, d, J=5Hz), 8.5(2H, d, J=5Hz), 9.47(1H, d, J=8Hz)

The following compounds of Examples 2-29 were synthesized in the samemanner as in Example 1.

EXAMPLE 2 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-ethoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate

MP: 170° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1640, 1620, 1535

NMR(DMSO-d₆)δ: 1.2(3H, t, J=7Hz), 4.08(2H, q, J=7Hz), 5.01(3H, bs),5.50(1H, dd, J=5 & 7Hz), 6.7(1H, s), 7.19(2H, br), 7.39(2H, d, J=5Hz),8.48(2H, d, J=5Hz), 9.43(1H, d, J=7Hz)

EXAMPLE 3 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate

MP: 170° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1610, 1535

NMR(DMSO-d₆)δ: 4.3(2H, bs), 4.95-5.1(3H, m), 5.51(1H, dd, J=4.5 & 8Hz),6.81(1H, s), 7.2(2H, br), 7.39(2H, d, J=5Hz), 8.49(2H, d, J=5Hz),11.71(1H, d, J=8Hz)

EXAMPLE 4 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxylato-1-methylethoxyimino)acetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate

MP: 180° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1560-1680, 1530

NMR(DMSO-d₆)δ: 1.38(3H, s), 1.45(3H, s), 5.0(3H, bs), 5.55(1H, dd, J=4.5& 8Hz), 6.69(1H, s), 7.17(2H, bs), 7.38(2H, d, J=5Hz), 8.48(2H, d,J=5Hz), 11.44(1H, d, J=8Hz)

EXAMPLE 5 Disodium7β-[2-(2-aminothiazol-4-yl)-(z)-2-(1carboxylatovinyloxyimino)acetamido]-3-(4-pyridyl-methoxy)-3-cephem-4-carboxylate

MP: 175° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1600, 1535

NMR(DMSO-d₆)δ4.86(1H, bs), 5.01(3H, bs), 5.16(1H, bs), 5.53(1H, m),6.90(1H, s), 7.26(2H, bs), 7.4(2H, d, J=5Hz), 8.49(2H, d, J=5Hz)

EXAMPLE 6 Sodium7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2ethoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate

MP: 190° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1600, 1530, 1410

NMR(DMSO-d₆)δ: 1.25(3H, t, J=8Hz), 3.4(2H, bs), 4.16(2H, m), 5.0(3H,bs), 5.55(2H, dd, J=5 & 8Hz), 7.42(2H, d, J=5Hz), 8.2(2H, bs), 8.5(2H,d, J=5Hz), 9.42(1H, d, J=8Hz)

EXAMPLE 77β-(D-2-amino-2-phenylacetamido)-3-(4-pyridylmethoxy)-3-cephem-4-carboxylicacid

MP: 165° C. (decomposed)

IR(KBr)cm ⁻¹ : 3430, 3050, 1755, 1670, 1600, 1410

NMR(DMSO-d6)δ: 3.45(2H, bs), 4.52(2H, bs), 4.9(1H, d, J=5Hz), 4.99(1H,bs), 5,44(1H, d, J=5Hz), 7.44(7H, m), 8.5(2H, d, J=4Hz), 8.76(1H, br)

EXAMPLE 8 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(3-pyridylmethoxy)-3-cephem-4-carboxylate

MP: 175° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1580-1680, 1540

NMR(DMSO-d₆ +D₂ O)δ: 3.39(2H, bs), 3.86(3H, s), 5.0(3H, bs), 5.49(1H, d,J=4Hz), 6.77(1H, s), 7.37(1H, dd, J=4.5 & 8Hz), 7.9(1H, d, J=8Hz),8.48(1H, d, J=4.5Hz), 8.58(1H, s)

EXAMPLE 9 Sodium7β-[2-(2-aminothiazol-4-y1)-(Z)-2-methoxyiminoacetamido]-3-(2-pyridylmethoxy)-3-cephem-4-carboxylateMP: 140° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1600-1680, 1530

NMR(DMSO-D₆ +D₂ O)δ: 3.08, 3.4(2H, ABq, J=13Hz), 3.88(3H, s),5.05-5.25(1H, m), 5.4-5.75(3H, m), 6.77(1H, s), 7.8-8.25(2H, m),8.57(1H, d, J=6.5Hz), 8.99(1H, d, J=6Hz)

EXAMPLE 10 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino-acetamido]-3-[2-(2-pyridyl)ethoxy]-3cephem-4-carboxylate

MP: 180° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1580-1680, 1540

NMR(DMSO-D₆ +D₂ O)δ: 3.04(2H, t, J=6.5Hz), 3.21(2H, bs), 3.86(3H, s),4.2(2H, t, J=6.5Hz), 4.97(1H, d, J=5Hz), 5.46(1H, d, J=5Hz), 6.77(1H,s), 7.0-7.5(2H, m), 7.67(1H, d, J=8Hz), 8.45(1H, d, J=5Hz)

EXAMPLE 11 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[1-(4-pyridyl)ethoxy]-3-cephem-4-carboxylate

MP: 175-180° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1660, 1600, 1530

EXAMPLE 12 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-cyanobenzyloxy)-3-cephem-4-carboxylate

MP: 175-180° C. (decomposed)

IR(KBr)cm⁻¹ : 2230, 1760, 1610, 1530, 1360

NMR(DMSO-d₆)δ: 3.4(m), 3.88(3H, s), 4.95-5.1(3H, m), 5.4(1H, dd, J=5 &8Hz), 6.75(1H, s), 7.27(2H, br), 7.62(2H, d, J=8Hz), 7.79(2H, d, J=8Hz),9.5(1H, d, J=8Hz)

EXAMPLE 13 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-nitrobenzyloxy)-3-cephem-4-carboxylate

MP: 165-170° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1600, 1520, 1360

NMR(DMSO-d₆)δ: 3.4(m), 3.86(3H, s), 5.02(1H, d, J=5Hz), 5.12(2H s)5.55(1H m) 6.75(1H, s), 7.25(2H, br), 7.72(2H, d, J=9Hz), 8.2(2H, d,J=9Hz), 9.5(1H, bd, J=8Hz)

EXAMPLE 14 Sodium7β-[2-(2-aminothiazol-4-y1)-(Z)-2-methoxyiminoacetamido]-3-(4-carbamoylbenzyloxy)-3-cephem-4carboxylate

MP: 190-195° C. (decomposed)

IR(KBr)cm ⁻¹ : 1755, 1660, 1615, 1530

NMR(DMSO-d₆)δ: 3.4(2H, br), 3.85(3H, s), 4.98(1H, d, J=4Hz), 5.02(2H,bs), 5.5(1H, dd, J=4 & 8Hz), 6.74(1H, s), 7.25(2H, bs), 7.47(2H, d,J=8Hz), 7.85(2H, d, J=8Hz), 7.99(2H, s), 9.4(1H, d, J=8Hz)

EXAMPLE 15 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(thiazol-4-ylmethoxy)-3-cephem-4carboxylate

MP: 150-155° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1620, 1535, 1415, 1370

NMR(DMSO-d₆)δ: 3.4(m), 3.82(3H, s), 4.95(1H, d, J=5Hz), 5.08(2H, s),5,45(1H, dd, J=5 & 9Hz), 6.71(1H, s), 7.18(2H, br), 7.72(1H, s),9.02(1H, s), 9.45(1H, d, J=9Hz)

EXAMPLE 16 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-methylthiazol-2-ylmethoxy)-3-cephem-4-carboxylate

MP: 175-180° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1615, 1530, 1365

NMR(DMSO-d₆)δ: 2.35(3H, s), 3.4(m), 3.85(3H, s), 5.0(1H, d, J=5Hz),5.21(2H, s), 5.5(1H, m), 6.72(1H, s), 7.22(3H, bs), 9.5(1H, bd, J=8Hz)

EXAMPLE 17 Sodium7β-[2-(2-aminothiazol-4-y1)-(Z)-2-methoxyiminoacetamido]-3-(2-methylthiazol-5-ylmethoxy)-3-cephem-4-carboxylate

MP: 170-175° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1615, 1535, 1360

NMR(DMSO-d₆)δ: 2.62(3H, s), 3.4(m), 3.85(3H, s), 4.97(1H, d, J=5Hz),5.15(2H, s), 5.5(1H, m), 6.72(1H, s), 7.25(2H, br), 7.55(1H, s), 9.5(1H,bd, J=8Hz)

EXAMPLE 18 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1,2,3-thiadiazol-4-yl)-3-cephem-4carboxylate

MP: 160-165° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1620, 1535, 1370

NMR(DMSO-d₆)δ: 3.4(m), 3.85(3H, s), 4.98(1H, d, J=5Hz), 5.5(3H, m),6.72(1H, s), 7.2(2H, br), 9.35(1H, s), 9.46(1H, d, J=9Hz)

EXAMPLE 19 Sodium7B-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methylimidazol-2-ylmethoxy)-3-cephem-4-carboxylate

MP: 160-165° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1660, 1610, 1535, 1360

NMR(DMSO-d₆)δ: 3.4(m), 3.72(3H, s), 3.86(3H, s), 4.95-5.05(3H, m),5.5(1H, m), 6.75(1H, s), 6.82(1H, s), 7.12(1H, s), 7.22(2H, br), 9.5(1H,br)

EXAMPLE 20 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(5S)-(2-pyrrolidon-5-ylmethoxy)]-3-cephem-4-carboxylate

MP: 190-195° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1670, 1530, 1365

NMR(DMSO-d₆)δ: 1.9-2.3(4H, m), 3.4(m), 3.6(2H, m), 3.88(3H, s), 4.1(1H,m), 5.04(1H, d, J=5Hz), 5.5(1H, dd, J=5 & 8Hz), 6.75(1H, s), 7.25(2H,br), 9.32(1H, br), 9.5(1H, d, J=8Hz)

EXAMPLE 21 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(5RS)-(2-pyrrolidon-5-ylmethoxy)]-3-cephem-4-carboxylate

MP: 185-190° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1670, 1530, 1365

NMR(DMSO-d₆)δ: 1.9-2.3(4H, m), 3.4(m), 3.5-3.7(2H, m), 3.85(3H, s),4.0(1H, m), 5.0(1H, d, J=5Hz), 5.45(1H, m), 6.75(1H, s) 7.2(2H, br),8.8-9.6(2H, m)

EXAMPLE 22 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3-(4-carbamoylbenzyloxy)-3-cephem-4-carboxylate

MP: 185-190° C. (decomposed)

IR(KBr)cm⁻¹ : 1755, 1660, 1615, 1530

NMR(DMSO-d₆)δ: 3.36(2H, br), 4.3(2H, br), 4.98(1H, d, J=4Hz), 5.0(2H,s), 5.5(1H, dd, J=4 & 8Hz), 6.8(1H, s), 7.26(2H, bs), 7.44(2H, d,J=8Hz), 7.85(2H, d, J=8Hz), 8.02(2H, s), 11.57(1H, d, J=8Hz), 6.72(1H,s), 7.3(4H, m), 7.84(2H, d, J=8Hz), 9.45(1H, bd, J=8Hz)

EXAMPLE 23 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3-benzyloxy-3-cephem-4-carboxylate

MP: 180-185° C.

IR(KBr)cm⁻¹ : 1760, 1610, 1540, 1410, 1370

NMR(DMSO-d₆)δ: 3.4(m), 4.28(2H, s), 4.95(3H, m), 5.5(1H, m), 6.82(1H,s), 7.38(5H, m)

EXAMPLE 24 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3-[(5RS)-(2-pyrrolidon-5-yl-methoxy)]-3-cephem-4-carboxylate

MP: 155-160° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1670, 1600, 1530, 1360

NMR(DMSO-d₆)δ: 1.9-2.2(4H, m), 3.4(m), 3.5-3.7(2H, m), 3.9-4.1(1H, m),4.3(2H, s), 5.02(1H, d, J=5Hz), 5.5(1H, m), 6.82(1H, s), 7.2(2H, br),8.8-9.2(1H, m), 11.6(1H, br)

EXAMPLE 25 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3-(thiazol-4-ylmethoxy)-3-cephem-4-carboxylate

MP: 70-80° C. (decomposed)

IR(KBr)cm⁻¹ : 1760 1610 1535 1415 1380

NMR(DMSO-d₆)δ: 3.4(m), 4.28(2H, s), 4.96(1H, d, J=5Hz), 5.09(2H, br),5.5(1H, m), 6.82(1H, s), 7.18(2H, br), 7.78(1H, s), 9.06(1H, s)

EXAMPLE 26 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3-(4-methyl-thiazol-2-ylmethoxy)-3-cephem-4-carboxylate

MP: 175-180° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1610, 1530, 1410, 1370

NMR(DMSO-d₆)δ: 2.34(3H, s), 3.4(m), 4.3(2H, bs), 5.0(1H, d, J=5Hz),5.2(2H, bs), 5.5(1H, m), 6.82(1H, s), 7.2(3H, bs)

EXAMPLE 27 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3-(2-methylthiazol-5-ylmethoxy)-3-cephem-4-carboxylate

MP: 170-175° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1610, 1530, 1410

NMR(DMSO-d )δ: 2.62(3H, s), 3.4(m), 4.3(2H, bs), 4.98(1H, d, J=5Hz),5.14(2H, s), 5.5(1H, m), 6.82(1H, s), 7.25(2H, br), 7.55(1H, s)

EXAMPLE 28 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3-(1,2,3-thiadiazol-4-ylmethoxy)-3-cephem-4-carboxylate

MP: 160-165° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1600, 1535, 1410, 1370

NMR(DMSO-d₆)δ: 3.4(m), 4.28(2H, s), 4.96(1H, d, J=5Hz), 5.45(3H, m),6.8((1H, s), 7.18(2H, br), 9.31(1H, s)

EXAMPLE 29 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxymethoxyiminoacetamido]-3-(1-methylimidazol-2-ylmethoxy)-3-cephem-4-carboxylate

MP: 155-160° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1620, 1535, 1410, 1370

NMR(DMSO-d₆)δ: 3.4(m), 3.7(3H, s), 4.28(2H, s), 4.9-5 1(3H, m), 5.4(1H,m), 6.82(2H, s), 7.12(1H, s), 7.16(2H, br)

EXAMPLE 30 Disodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-carboxylatobenzyloxy)-3-cephem-4-carboxylate

1.14 g (1.5 mmol) of p-methoxybenzyl 7β-[2-(2-trityl-aminothiazol-4-yl)-(Z)-2-methoxyacetamido]-3-hydroxy-3-cephem-4-carboxylate and 472 mg(1.8 mmol) of triphenylphosphine were dissolved in 20 ml oftetrahydrofuran, and a solution of 537.1 mg (1.8 mmol) of benzhydrylp-hydroxymethylbenzoate in 10 ml of tetrahydrofuran was added thereto at-20° C. under nitrogen atmosphere. Then, a tetrahydrofuran solution (10ml) of 0.28 ml (1.8 mmol) of diethylazodicarboxylate was added theretoat the same temperature, and the mixture was stirred for 20 minutes.Ethyl acetate was added to the reaction solution. The solution waswashed sequentially with water, a 1N hydrochloric acid aqueous solution,a saturated sodium hydrogencarbonate aqueous solution and a saturatedsodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent wad distilled off and the residue was purified by silica gelcolumn chromatography (Wakogel C-300, elution withdichloromethane-chloroform) to obtain 1.28 g (yield: 80.5%) ofp-methoxybenzyl7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-diphenylmethoxycarbonyl-benzyloxy)-3-cephem-4-carboxylateas a powder. 1.2 g (1.13 mmol) of this powder was dissolved in 12 ml ofanisole. 12 ml of trifluoroacetic acid was added thereto under coolingwith ice, and the mixture was stirred for 30 minutes at the sametemperature. The solvent was distilled off and isopropyl ether was addedto the residue to obtain the trifluoroacetate of the above-identifiedcompound as a powder. This powder was dissolved in water and adjusted topH7.6 with a sodium hydrogencarbonate aqueous solution. The solution waspurified by reversed phase column chromatography (Chemco LC-SORD,SP-β-ODS, elution with 10% methanol aqueous solution) and freeze-driedto obtain 312 mg (yield: 53.8%) of the above-identified compound.

MP: 190-195° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1600, 1540, 1380

NMR(DMSO-d₆)δ: 3.4(m), 3.82(3H, s), 4.98(3H, m), 5.5(1H, m)

EXAMPLE 31

Trisodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3-(4-carboxylatobenzyloxy)-3-cephem-4-carboxylate

The above-identified compound was synthesized in the same manner as inExample 30.

MP: 160-165° C. (decomposed)

IR(KBr)cm⁻¹ : 1760 1620 1535, 1380

NMR(DMSO-d₆ +D₂ O)δ: 3.35(2H, m), 4.48(2H, br), 4.98(3H, m), 5.48(1H, d,J=5Hz), 6.82(1H, s), 7.34(2H, d, J=9Hz), 7.84(2H, d, J=9Hz)

EXAMPLE 327β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

492 mg (0.577 mmol) of p-methoxybenzyl 7β-[2-(2-tritylaminothizol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylateprepared in the same manner as in Example 1 was dissolved in 58 ml ofacetone, and 2.1 ml (34 mmol) of methyl iodide was added thereto. Themixture was stirred at room temperature overnight. The solvent wasdistilled off and triturated with ethyl ether to obtain 541 mg (yield:94.2%) of p-methoxybenzyl7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylateiodide as a yellow powder. 519 mg (0.522 mmol) of this powder wasdissolved in 2.9 ml of dichloromethane and 0.92 ml of anisole, and 4.6ml of trifluoroacetic acid was added thereto under cooling with ice. Themixture was stirred for 1 hour at the same temperature. The solvent wasdistilled off and isopropyl ether was added to the residue to obtain thetrifluoroacetate of the above-identified compound as a powder. Thispowder was dissolved in water and adjusted to pH6.5 with a sodiumhydrogencarbonate aqueous solution. The solution was purified byreversed phase column chromatography (Chemco LC-SORB, SP-β-ODS, elutionwith 30% methanol aqueous solution), and freeze-dried to obtain 88.5 mg(yield: 33.6%) of the above-identified compound.

MP: 140° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1650, 1610, 1535

NMR(DMSO-d₆)δ: 3.84(3H, s), 4.33(3H, bs), 5.0(1H, d, J=5Hz), 5.27(2H,bs), 5.5(1H, dd, J=5 & 8Hz), 6.76(1H, s), 7.22(2H, br), 8.16(2H, d,J=4Hz), 9.93(2H, d, J=4Hz), 9.49(1H, d, 8Hz)

The following compounds of Examples 33-49 were synthesized in the samemanner as in Example 32.

EXAMPLE 33

7β-[2-(2-aminothiazol-4-yl)-(Z)-2-ethoxyiminoacetamido]-3-[1-methyl-4-pyridiniomethoxy-3-cephem-4-carboxylate

MP: 150° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1645, 1620, 1530

NMR(DMSO-d₆)δ: 1.22(3H, t, J=7Hz), 4.09(2H, q, J=7Hz), 4.32(3H, bs),4.99(1H, d, J=4.5Hz), 5.25(2H, bs), 5.51(1H, dd, J=4.5 & 8Hz), 6.71(1H,s), 7.18(2H, br), 8.13(2H, d, J=5Hz), 8.92(2H, d, J=5Hz), 9.42(1H, d,J=8Hz)

EXAMPLE 347β[2-(2-aminothiazol-4-yl)-(Z)-2-benzyloxyiminoacetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 165° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1660, 1645, 1610, 1530

NMR(DMSO-d₆)δ: 4.3(3H, bs), 4.98(1H, d, J=4.5Hz), 5.13(2H, bs), 5.23(2H,bs), 5.5(1H, dd, J=4.5 & 8Hz), 6.72(1H, s), 7.2(2H, br), 7.33(5H, bs),8.12(2H, d, J=6Hz), 8.9(2H, d, J=6Hz), 9.55(1H, d, J=8Hz)

EXAMPLE 35 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 130° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1600, 1540

NMR(DMSO-d₆)δ: 3.48, 3.78(2H, ABq, J=17Hz), 4.58(3H, s), 5.23(1H, d,J=4.5Hz), 5.3(2H, s), 5.71(1H, d, J=4.5Hz), 7.03(1H, s), 8.03(2H, d,J=5Hz), 8.71(2H, d, J=5Hz)

EXAMPLE 36 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxylato-1-methylethoxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 155° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1640, 1585, 1530

NMR(DMSO-d₆ +D₂ O)δ: 4.86(1H, bs), 5.01(3H, bs), 5.16(1H, bs), 5.53(1H,m), 6.9(1H, s), 7.26(2H, br), 7.4(2H, d, J=5Hz), 8.49(2H, d, J=5Hz)

EXAMPLE 37 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-(1carboxylatovinyloxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 145° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1640, 1595, 1530

NMR(DMSO-d₆ +D20)δ: 3.45(2H, bs), 4.29(3H, bs), 4.9(1H, bs), 5.01(1H, d,J=4.5Hz), 5.16(1H, bs), 5.52(1H, d, J=4.5Hz), 6.92(1H, s), 8.1(2H, d,J=6Hz), 8.8(2H d, J=6Hz)

EXAMPLE 38 Sodium7δ-[2-(2-aminothiazol-4-yl)-(Z)-2-(α-carboxylato-3,4-dihydroxybenzyloxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate(diastereisomer A)

MP: 170° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1570, 1530

EXAMPLE 39 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-(α-carboxylato-3,4-dihydroxybenzyloxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate(diastereisomer B)

MP: 175° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1570, 1530

EXAMPLE 40 Sodium7β-[2-(2-aminothiazol-4-yl}-(Z)-2-(2carboxylatomethylbenzyloxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 145° C.

IR(KBr)cm ⁻¹ : 1760, 1645, 1585, 1535

NMR(DMSO-d₆ +D₂ O)δ: 6 3.34(2H, s), 4.27(3H, s), 4.98(1H, d, J=4.5Hz),5.23(2H, bs), 5.5(1H, d, J=4.5Hz), 6.73(1H, s), 7.13(4H, br), 8.1(2H,bd, J=5Hz), 8.79(2H, bd, J=5Hz)

EXAMPLE 417β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-ethoxyiminoacetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 140° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1670, 1640, 1610, 1520

NMR(DMSO-d₆)δ: 1.25(3H, t, J=8Hz), 3.53(2H, bs), 4.16(2H, m), 4.32(3H,s), 4.98(1H, d, J=5Hz), 5.23(2H, bs), 5.55(1H, dd, J=5 & 8Hz), 8.13(2H,d, J=5Hz), 8.92(2H, d, J=5Hz), 9.43(1H, d, J=9Hz)

EXAMPLE 427β-(D-2-amino-2-phenylacetamido)-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 130° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1665, 1640, 1600

NMR(DMSO-d₆ +D₂ O)δ: 3.4(2H, bs), 4.3(3H, s), 4.4(2H, bs), 4.9(1H, m),5.06(1H, s), 5.4(1H, s), 7.32(5H, m). 8.1(2H, m), 8.85(2H, m)

EXAMPLE 437β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-3-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 155° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1580-1680, 1535

NMR(DMSO-d₆)δ: 3.82(3H, s), 4.34(3H, s), 4.95(1H, d, J=4.5Hz), 5.13(2H,s), 5.45(1H, dd, J=4.5 & 7.5Hz), 6.71(1H, s), 7.17(2H, br), 7.9-8.2(1H,m), 8.57(1H, d, J=8Hz), 8.89(1H, d, J=5Hz), 9.32(1H, bs), 9.43(1H, d,J=7.5Hz)

EXAMPLE 447β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-2-pyridiniomethoxy)-3-cephem--carboxylate

MP: 150° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1660, 1630, 1600

NMR(DMSO-d₆)δ: 3.53(2H, bs), 3.84(3H, s), 4.33(3H, bs), 4.97(1H, d,J=4.5Hz), 5.3-5.6(3H, m), 6.74(1H, s), 7.2(2H, br), 7.85-8.15(1H, m),8.15-8.4(1H, m), 8.4-8.7(1H, m), 8.9-9.2(1H, m), 9.47(1H, bd, J=8Hz)

EXAMPLE 457β-[2-(2-aminothiazol-4-yl)-(Z)-2-(2-fluoroethoxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP:148-151° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1600 1680, 1530

NMR(DMSO-d₆)δ: 4.00-4.93(7H, m), 4.98(1H, d, J=5Hz), 5.23(2H, bs),5.50(1H, dd, J=5 & 8Hz), 6.74(1H, s), 7.20(2H, br), 8.11(2H, d, J=5Hz),8.90(2H, d, J=5Hz), 9.48(1H, d, J=8Hz)

EXAMPLE 467β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-propyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 128-130° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1560-1700, 1530

NMR(DMSO-d₆)δ: 0.85(3H, t, J=7Hz), 1.6-2.2(2H, m), 3.83(3H, s),4.3-4.7(2H, m), 4.9(1H, d, J=4.5Hz), 5.26(2H, bs), 5.46(1H, dd, J=4.5 &8Hz), 6.72(1H, s), 7.2(2H, bs), 8.16(2H, d, J=5Hz), 9.03(2H, d, J=5Hz),9.45(1H, d, J=8Hz)

EXAMPLE 477β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-allyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 145-150° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1560-1700, 1530

NMR(DMSO-d₆)δ: 3.85(3H, s), 5.0(1H, d, J=4.5Hz), 5.1-5.6(7H, m), 5.96.4(1H, m), 6.75(1H, s), 7.18(2H, bs), 8.1-8.3(2H, m), 8.8-9.1(2H, m)

EXAMPLE 487β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[1-(1-methyl-4-pyridinio)ethoxy]-3-cephem-4-carboxylate

MP: 120-122° C. (decomposed)

IR(KBr)cm⁻¹ : 1755 1640 1610 1530

EXAMPLE 497β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-carbamoylmethyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 130-135° C. (decomposed)

IR(KBr)cm ⁻¹ : 1760, 1560-1720, 1530

NMR(DMSO-d₆ +D₂ O)δ: 3.1-3.6(2H, m), 5.02(1H, d, J=4.5Hz), 5.35(2H, bs),5.53(1H, d, J=4.5Hz), 6.78(1H, s), 8.19(2H, d, J=5Hz), 8.83(2H, d,J=5Hz)

EXAMPLE 50 Sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido-3-(1-carboxylatomethyl-4pyridiniomethoxy)-3-cephem-4-carboxylate

800 mg(0.938 mmol) of p-methoxybenzyl 7β-[2-(2tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylateobtained in the same manner as in Example 1 was dissolved in 93 ml ofacetone, and 3.34 g (9.49 mmol) of benzhydryl iodoacetate and a fewdrops of N,N-dimethylformamide were added thereto. The mixture wasstirred overnight at room temperature. The solvent was distilled off,and the residue was triturated with ethyl ether to obtain 1.33 g of apowder. 1.3 g of this powder was dissolved in 6 ml of dichloromethaneand 1.3 ml of anisole, and 9 ml of trifluoroacetic acid was addedthereto under cooling with ice. The mixture was stirred for 1 hour atthe same temperature. The solvent was distilled off and isopropyl etherwas added to the residue to obtain the trifluoroacetate of theabove-identified compound. The trifluoroacetate was dissolved in waterand adjusted to pH7.0 with a sodium hydrogencarbonate aqueous solution.Then, the solution was purified by reversed phase column chromatography(Chemco LC-SORB, SP-β-ODS, elution with 30% methanol aqueous solution),and freeze-dried to obtain 133 mg (yield: 21.8%) of the above-identifiedcompound.

MP: 150° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1640, 1535

NMR(DMSO-d₆)δ: 3.83(3H, s), 4.93(2H, bs), 5.03(1H, d, J=4.5Hz), 5.27(2H,bs), 5.52(1H, dd, J=4.5 & 8Hz), 6.74(1H, s), 7.22(2H, bs), 8.07(2H, d,J=6Hz), 8.78(2H, d, J=6Hz), 9.53(1H, d, J=8Hz)

The following compounds of Examples 51 and 52 were synthesized in thesame manner as in Example 50.

EXAMPLE 51 Sodium7β-[2-(2-aminothiazol-4-Y1)-(Z)-2-ethoxyiminoacetamido]-3-(1-carboxylatomethyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate

MP: 150° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1640, 1530

NMR(DMSO-d₆)δ: 1.22(3H, t, J=7Hz), 4.08(2H, q, J=7Hz), 4.9(2H, bs),5.01(1H, d, J=4.5Hz), 5.25(2H, bs), 5.52(1H, dd, J=4.5 & 7Hz), 6.71(1H,s), 7.2(2H, bs), 8.05(2H, d, J=5Hz), 8.76(2H, d, J=5Hz), 9.46(1H, d,J=7Hz)

EXAMPLE 52 Disodium7β-[2-(2-aminothiazol-4-yl)-2-carboxylatomethoxyiminoacetamido]-3-(1-carboxylatomethyl-4-pyridinio-methoxy)-3-cephem-4-carboxylate

MP: 150° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1580-1700, 1540

NMR(DMSO-d₆)δ: 3.5, 3.8(2H, ABq, J=18Hz), 4.59(2H, s), 5.18(1H, d,J=4Hz), 5.21(2H, s), 5.35(2H, s), 5.73(1H, d, J=4Hz), 7.06(1H, s),8.07(2H, d, J=6Hz), 8.7(2H, d, J=6Hz)

EXAMPLE 537β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(3,4-dihydroxy-1-methyl-6-pyridiniomethoxy)-3-cephem-4-carboxylate

340 mg (0.446 mmol) of p-methoxybenzyl 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate and 146mg (0.557 mmol) of triphenylphosphine were dissolved in 7 ml oftetrahydrofuran, and a solution of tetrahydrofuran (3.5 ml) of 170 mg(0.446 mmol) of 4,5-bis(4-methoxybenzyloxy)-2-hydroxymethylpyridine wasadded thereto at -20° C. under nitrogen atmosphere. Then, a solution of0.087 ml (0.55 mmol) of diethylazodicarboxylate in 3.5 ml oftetrahydrofuran was dropwise added to the solution at -20° C., and themixture was stirred for 1 hour at the same temperature. 30 ml ofethylacetate was added thereto. The solution was washed sequentiallywith water, a 1N hydrochloric acid aqueous solution, a saturated sodiumhydrogencarbonate aqueous solution and a saturated sodium chlorideaqueous solution and dried over magnesium sulfate. The solvent wasdistilled off, and the residue was purified by silica gel columnchromatography (Wakogel C-300, elution with 1-2% methanol-chloroform) toobtain 325 mg (yield: 64.8%) of p-methoxybenzyl7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-[3,4-bis(4-methoxybenzyloxy)-6-pyridylmethoxy]-3-cephem-4-carboxylate as a powder. 325 mg (0.289mmol) of this powder was dissolved in 28 ml of methylene chloride, and asolution of 0.067 ml (0.592 mmol) of methyltrilrate in 2 ml of methylenechloride was dropwise added thereto at -20° C. under nitrogenatmosphere. The mixture was stirred for 1 hour at room temperature. Thesolvent was distilled off, and the residue was triturated to obtain 355mg (yield: 95.2%) of p-methoxybenzyl 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-[3,4-bis(4-methoxybenzyloxy)-1-methyl-6-pyridiniomethoxy]-3-cephem-4-carboxylatetrifluoromethanesulfonate as a powder. 355 mg (0.275 mmol) of thispowder was dissolved in 429 mg (2.79 mmol) of3-methyl-4-methylthiophenol, 2 ml of methylene chloride and 0.34 ml (2.5mmol) of thioanisole, and 2 ml of trifluoroacetic acid was added theretounder cooling with ice. The mixture was stirred for 1 hour at roomtemperature. The solvent was distilled off, and ethyl ether was added tothe residue to obtain the trifluoroacetate of the above-identifiedcompound as a powder. This powder was dissolved in water and insolubleswere filtered off. The filtrate was purified by reversed phase columnchromatography (Chemco LC-SORB, SP-β-ODS, elution with 30% methanolaqueous solution) and freeze-dried to obtain 28.1 mg (yield: 19%) of theabove-identified compound.

MP: 150-160° C. (decomposed)

IR(KBr)cm⁻¹ : 3350, 1760, 1670, 1630, 1560, 1535

NMR(DMSO-d₆)δ: 3.68(3H, s), 3.86(3H, s), 5.07(2H, s), 5.18(1H, d,J=5Hz), 5.61(1H, dd, J=5 & 8Hz), 6.40(1H, s), 6.84(1H, s), 7.26(2H, br),7.50(1H, s), 9.60(1H, d, J=8Hz)

EXAMPLE 54 Sodium 7β-[2-(2-aminothiazol-4-y1)-(Z)-2-(1-carboxylato-1-methylethoxyimino)acetamido]-3-(3,4-dihydroxy-1-methyl-6-pyridiniomethoxy)-3-cephem-4-carboxylate

The above-identified compound was synthesized in the same manner as inExample 53.

MP: 170-180° C. (decomposed)

IR(KBr)cm^(-1:) 3450, 1765, 1670, 1635, 1560

NMR(DMSO-d₆)δ: 1.44(3H, s), 1.46(3H, s), 3.68(3H, s), 5.07(2H, s),5.20(1H, d, J=4Hz), 5.68(1H, dd, J=4 & 8Hz), 6.41(1H, s), 6.80(1H, s),7.33(2H, br), 7.51(1H, s), 9.45(1H, d, J=8Hz)

EXAMPLE 55 Pivaloyloxymethyl7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido-3-(4-cyanobenzyloxy)-3-cephem-4-carboxylate

57.4 mg (0.38 mmol) of chloromethyl pivalate was dissolved in 2 ml ofacetone, and 63 mg (0.42 mmol) of sodium iodide was added thereto. Themixture was heated for 30 minutes at 50° C., and 4 ml of ethyl ether wasadded thereto. Insolubles were filtered off and the solvent wasdistilled off. Then, the residue was dissolved in 1 ml ofN,N-dimethylformamide. 100 mg (0.217 mmol) of sodium7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-cyanobenzyloxy)-3-cephem-4-carboxylateprepared in the same manner as in Example 12 was dissolved in 1 ml ofN,N-dimethylformamide. The above solution was added to this solutionunder cooling with ice and stirred for 30 minutes at room temperature.Water and ethyl acetate was added to the reaction solution, and theethyl acetate layer was separated and washed sequentially with asaturated sodium hydrogencarbonate aqueous solution and a saturatedsodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent was distilled off and the residue was triturated with ethylether to obtain 24.8 mg (yield: 21.2%) of the above-identified compound.

MP: 120-123° C. (decomposed)

IR(KBr)cm⁻¹ : 1780, 1750, 1675, 1620, 1530

NMR(DMSO-d₆)δ: 1.16(9H, s), 3.78(2H, s), 3.86(3H, s), 5.11(2H, s),5.23(1H, d, J=4Hz), 5.73(1H, dd, J=4 & 8Hz), 5.79, 5.89(2H, ABq, J=6Hz),6.81(1H, s), 7.24(2H, br), 9.64(1H, d, J=8Hz)

The following compounds of Examples 56-57 were synthesized in the samemanner as in Example 55.

EXAMPLE 56 Pivaloyloxymethyl 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-nitrobenzyloxy)3-cephem-4-carboxylate

MP: 122-125° C. (decomposed)

IR(KBr)cm⁻¹ : 1780, 1750, 1680, 1615, 1520

NMR(DMSO-d₆)δ: 1.11(9H, s), 3.64-3.94(5H, m), 5.23(1H, d, J=4Hz),5.40(2H, s), 5.63(1H, dd, J=4 & 8Hz), 5.81, 5.89(2H, ABq, J=6HZ),6.85(1H, s), 7.28(2H, br), 7.72(2H, d, J=8Hz), 8.29(2H, d, J=8Hz),9.58(1H, d,J=8Hz)

EXAMPLE 57 Pivaloyloxymethyl7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1,2,3-thiadiazol-4-yl-methoxy)-3-cephem-4-carboxylate

MP: 115-120° C. (decomposed)

IR(KBr)cm⁻¹ : 1780, 1750, 1675, 1615, 1535

NMR(DMSO-d₆)δ: 1.10(9H, s), 3.8-4.0(5H, m), 5.22(1H, d, J=4Hz),5.6-5.9(5H, m), 6.85(1H, s), 7.3(1H, br), 9.24(1H, s),9.62(1H, d, J=8Hz)

The compounds of the present invention have excellent antibacterialactivities and are useful for treatment to bacterial infectiousness ofmammal including human.

What is claimed is:
 1. A cephalosporin derivative having the formula:##STR8## wherein R¹ is a substituted amino group selected from the groupconsisting of:(i) R⁴ --C(═N OR⁵)--CONH-- group, wherein R⁴ is a phenyl,naphthyl, furanyl, thienyl, thiazolyl, 1,2,4-thiadiazolyl, pyridyl,isothiazolyl, oxazolyl, pyrimidyl group which may be substituted; R⁵ isa hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, naphthyl, benzyl, phenethyl, naphthylmethyl, pyridyl,furanyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, isoquinolyl,quinolyl, oxazolyl, isoxazolyl, tetrazolyl group which may besubstituted; (ii) R⁴ --C(═C(--R⁶)--R⁷)--CONH-- group, wherein R⁴ is aphenyl, naphthyl, furanyl, thienyl, thiazolyl, 1,2,4-thiadiazolyl,pyridyl, isothiazolyl, oxazolyl, pyrimidyl group which may besubstituted; each of R⁶ and R⁷, which may be the same or different, is ahydrogen atom, a halogen atom or a C₁₋₆ alkyl, phenyl, naphthyl, benzyl,phenethyl, naphthylmethyl group which may be substituted; (iii) R⁸--(Z¹)_(n) --CH(--R⁹)--CONH-- group, wherein R⁸ is a C₁₋₆ alkyl, C₂₋₆alkenyl, phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl,tetrazolyl, oxazolyl group which may be substituted and R⁹ is a hydrogenatom, carboxyl group, an amino group, a sulfo group, a sulfamoyl group,a carbamoyl group, a hydroxyl group, a formyloxy group, a carbamoyloxygroup, Z¹ is an oxygen atom or a sulfur atom and n is 0 or 1; (iv) R¹⁰--CONH-- group, wherein R¹⁰ is pyridyl, imidazolyl, piperazinyl,thiazolyl or oxazolyl group which may be substituted; (v) ##STR9##wherein Z² is a carbon atom or a nitrogen atom and R¹¹ is a hydrogenatom, a C₁₋₆ alkyl, C₃₋₁₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, naphthyl, benzyl, phenethyl, naphthylmethyl, pyridyl, furanyl,thienyl, imidazolyl, thiazolyl, isothiazolyl, isoquinolyl, quinolyl,oxazolyl, isoxazolyl, tetrazolyl group which may be substituted; and(vi) ##STR10## wherein R¹² represents one or two substituents selectedfrom the group consisting of a hydrogen atom, a hydroxyl group, anacetoxy group and a halogen atom; X is an alkylene group, R² isimidazolyl or pyrrolidinyl which may be substituted by one or moresubstituents selected from the group consisting of a halogen atom, amethyl group, an ethyl group, a propyl group, a hydroxymethyl group, anaminomethyl group, a sulfomethyl group, a carboxymethyl group, acyanomethyl group, a fluoromethyl group, a chloromethyl group adifluoromethyl group, a trifluoromethyl group, a carbamoylmethyl group,an N-methylcarbamoylmethyl group, a sulfamoylmethyl group, an oxo groupan N-methylaminomethyl group, an amino group, a methylamino group, adimethylamino group, an ethylamino group, a methoxy group, an ethoxygroup, a fluoromethyl group, a difluoroethoxy group, a trifluoroethylgroup, a sulfamoyl group, a carboxyl group, a methoxycarbonyl group, acyano group, a nitro group, a vinyl group, an allyl group, a propargylgroup, an ethynyl group, an acetoxy group, a formyloxy group, acarbamoyloxy group, an N-methylcarbamoyloxy group, an acetamide group, aformamide group, an acetyl group, a fluoroacetyl group, a difluoroacetylgroup, a trifluoroaetyl group, a hydroxyl group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group, and a cyclohexyl group and R³ isa hydrogen atom, a negative charge or a residue of an ester which canform a pharmaceutically acceptable ester hydrolyzable in a living body;or a pharmaceutically acceptable salt thereof.
 2. The derivativeaccording to claim 1 wherein the substituent attached to R² is a halogenatom, a methyl group, an ethyl group, a propyl group, a sulfomethylgroup, a carboxymethyl group, a carbamoylmethyl group, a sulfamoylmethylgroup, an oxo group, an amino group, a sulfamoyl group, a carboxylgroup, an allyl group, a carbamoyloxy group or a hydroxyl group.